The envelope glycoprotein of HIV-1, gp120, is an established target for neutralizing antibodies that protect against infection. However, the capacity of monomeric or oligomeric gp120 to elicit protective immunity is limited by the structures of these molecules. One highly attractive target for protective immunity, the HIV co-receptor binding site, is largely absent from native gp120 and only becomes exposed in response to conformation changes induced by binding to the CD4 receptor. Consequently, the principal hypothesis of this project is that humoral responses to epitopes of an HIV envelope-receptor complex can protect against primary infection. We have already demonstrated that covalently cross-linked gp120-CD4 complexes elicit broadly neutralizing humoral responses. Accordingly, we will test our hypothesis with a primate SHIV challenge model and cross linked HIV-1 envelope-receptor complexes. We will first raise and characterize broadly neutralizing humoral immunity against the complexes in rhesus macaques. We will also examine T cell immunity and HIV- suppressive chemokine production, which will also be evaluated throughout the program project, in order to established whether neutralizing antibodies constitute the only responses relevant to virus inhibition. The immunized animals will then be challenged with SHIV 89.6 in order to assess whether there is a correlation between protection and the presence of an anti-complex response. Combined with information from the other components of the program project, this study should provide elementary information that can be applied toward the development of an effective HIV-1 subunit or subunit- boost vaccine strategy for humans.